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| Author(s): |
Thaís Sarraf Sabedot
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2018-03-12 |
| Examining board members: |
Houtan Noushmehr;
Mozart de Azevedo Marins;
Rodrigo do Tocantins Calado de Saloma Rodrigues;
Daniel Guimarães Tiezzi
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| Advisor: | Houtan Noushmehr |
| Abstract | |
Gliomas are heterogeneous tumors which contribute to their high mortality despite advancements in classification and treatment. As of 2016, the incorporation of IDH status and the integrity of chromosomes 1p and 19q to glioma classification have provided important clinical application for diagnostics and treatment; however, the search for molecular signatures that further refine glioma subtypes into more homogeneous subgroups is an ongoing effort. This study used the largest sample cohort (n=932) of adult gliomas to date, ranging from grades II to IV, in order to define gliomas subgroups using DNA methylation signatures, independent of histopathological grading. In total, 7 subtypes were identified: Classic-like, Mesenchymal-like, LGm6-GBM, PA-like, Codels, G-CIMP-low and G-CIMP-high. Most IDH -wildtype subgroups, e.g. Classic-like, Mesenchymal-like and LGm6-GBM, had low DNA methylation pattern and a poor outcome, typical of glioblastomas, the most aggressive phenotype of gliomas. An interesting finding was the identification of the PA-like subgroup within IDH -wildtype samples, which shared similar genomic features with pilocytic astrocytoma, a rare pediatric benign glioma, with a good overall survival (OS) among IDH -wildtype gliomas. Codels, which comprise IDH mutant gliomas with codeletion of chromosomes 1p/19q have the best OS across all adult gliomas. An important finding regarding IDH mutant gliomas with no codeletion of chromosomes 1p/19q, was the further segregation of the Glioma-CpG Island Methylator Phenotype (G-CIMP) into G-CIMP-low, with lower levels of DNA methylation and worse OS, and G-CIMP-high, characterized by higher DNA methylation profile and better OS. Interestingly, the degree of G-CIMP methylation (-low and -high) was associated with distinct alterations in regulatory elements and aberrant histone modifications at promoter regions of cell cycle genes. These findings consolidated the clinical importance of epigenetics, particularly DNA methylation, in gliomas, as well as the possibility that aggressive OS in G-CIMP-low may be driven by regulatory elements. Moreover, our results suggest that active enhancers that might be acting in gene regulation in G-CIMP-low provide more evidence of the regulatory elements that might be driving aggressiveness and proliferation in G-CIMP-low. This study aims 1) to identify and characterize adult diffuse glioma DNA methylation subtypes, and 2) evaluate the association of histone modifications with a more aggressive G-CIMP subtype (AU) | |
| FAPESP's process: | 16/06488-3 - Integrative epigenomic analysis of high and low Glioma-CpG island Methylator Phenotype (G-CIMP): characterization and methods development |
| Grantee: | Thaís Sarraf Sabedot |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |